Steroid-sensitive nephrotic syndrome (SSNS) represents one of the most frequent renal diseases in the first two decades of life. Steroid treatment is mandatory in affected patients and brings about a considerable morbidity. The disease mechanisms of SSNS remain unknown. Whereas in steroid-resistant nephrotic syndrome (SRNS) gene identification by positional cloning has significantly furthered the understanding of its pathomechanisms, until lately, not even a gene locus had been known for SSNS. We recently clinically characterized a cohort of 15 familial cases with SSNS, which were clinically and histologically indistinguishable from sporadic cases and most likely follow an autosomal recessive mode of inheritance. As a first step towards identifying a gene locus responsible for SSNS, total genome linkage analysis was performed in one larger consanguineous SSNS kindred. By homozygosity mapping a locus for SSNS on chromosome 2p was identified with a significant multipoint LOD score of Z[max] = 3.01. We thus identified the first gene locus (SSNS1) for SSNS. There was clear evidence for genetic locus heterogeneity indicating that there is at least one additional gene locus for SSNS. In the meantime we have extended the cohort to 30 multiplex SSNS families, the largest collection known worldwide We have developed a network to extend this number to over 60 families within one year. This will allow for identification of the SSNS1 gene and further genes responsible for SSNS. This proposal is aimed at the identification of the SSNS1 gene. Using well established methods of positional cloning, the responsible gene will be identified and its gene product characterized. Specifically, we propose to: i) refine the critical genetic region for SSNS1 to less than 800 kb, ii) perform a total genome search for additional loci, iii) identify the responsible SSNS1 gene by mutational analysis, and iv) characterize the function of the SSNS1 gene product. These studies will help to elucidate the pathogenesis of steroid-sensitive nephrotic syndrome.